Notes

Abstract:

Background: α-Synuclein (αS) is the major component of several types of brain inclusions including Lewy bodies, a
hallmark of Parkinson’s disease. Aberrant aggregation of αS also is associated with cellular demise in multiple
neurologic disorders collectively referred to as synucleinopathies. Recent studies demonstrate the induction of αS
pathology by a single intracerebral injection of exogenous amyloidogenic αS in adult non-transgenic and
transgenic mice expressing human αS. To further investigate the mechanism of pathology induction and evaluate
an experimental paradigm with potential for higher throughput, we performed similar studies in neonatal mice
injected with αS.
Results: In non-transgenic mice, we observed limited induction of neuronal αS inclusions predominantly 8 months
after brain injection of aggregated, amyloidogenic human αS. More robust inclusion pathology was induced in
transgenic mice expressing wild-type human αS (line M20), and inclusion pathology was observed at earlier time
points. Injection of a non-amyloidogenic (Δ71-82) deletion protein of αS was also able to induce similar pathology
in a subset of M20 transgenic mice. M20 transgenic mice injected with amyloidogenic or non-amyloidogenic αS
demonstrated a delayed and robust induction of brain neuroinflammation that occurs in mice with or without αS
pathological inclusions implicating this mechanism in aggregate formation.
Conclusions: The finding that a non-amyloidogenic Δ71-82 αS can induce pathology calls into question the simple
interpretation that exogenous αS catalyzes aggregation and spread of intracellular αS pathology solely through a
nucleation dependent conformational templating mechanism. These results indicate that several mechanisms may
act synergistically or independently to promote the spread of αS pathology.
Keywords: Amyloid, Neonatal, Parkinson’s disease, Pathology, α-Synuclein, Transgenic mice